Pharmacokinetic considerations in antipsychotic augmentation strategies: How to combine risperidone with low-potency antipsychotics

Progress in Neuro-Psychopharmacology & Biological Psychiatry 76 (2017) 101–106

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Pharmacokinetic considerations in antipsychotic augmentation strategies: How to combine risperidone with low-potency antipsychotics Michael Paulzen a,b,1, Georgios Schoretsanitis a,b,f,⁎,1, Benedikt Stegmann d, Christoph Hiemke g,h, Gerhard Gründer a,b, Koen R.J. Schruers e, Sebastian Walther f, Sarah E. Lammertz a,b, Ekkehard Haen c,d a

Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany JARA – Translational Brain Medicine, Aachen, Germany Clinical Pharmacology, Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany d Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany e Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands f University Hospital of Psychiatry, Bern, Switzerland g Department of Psychiatry and Psychotherapy, University Medical Center of Mainz, Germany h Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Germany b c

a r t i c l e

i n f o

Article history: Received 22 December 2016 Accepted 12 March 2017 Available online 14 March 2017 Keywords: Antipsychotics Risperidone Psychopharmacology Pharmacokinetics Therapeutic drug monitoring

a b s t r a c t Objectives: To investigate in vivo the effect of low-potency antipsychotics on metabolism of risperidone (RIS). Methods: A therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-OHRIS of 1584 patients was analyzed. Five groups were compared; a risperidone group (n = 842) and four co- medication groups; a group co-medicated with chlorprothixene (n = 67), a group with levomepromazine (n = 32), a group with melperone (n = 46), a group with pipamperone (n = 63) and a group with prothipendyl (n = 24). Plasma concentrations, dose-adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS and active moiety (RIS + 9OH-RIS; AM) as well as the metabolic ratios (9-OH-RIS/RIS; MR) were computed. Results: Differences in plasma concentrations were detected for AM and RIS. Pairwise comparisons revealed significant findings; RIS plasma concentrations were higher in co-medication groups than in monotherapy group. Chlorprothixene- and prothipendyl- medicated patients demonstrated no other differences. In the levomepromazine and melperone group plasma and C/D concentrations of AM and RIS were higher, while MRs were lower. For pipamperone, differences included higher C/D values of RIS and lower MRs. Conclusions: Alterations of risperidone metabolism suggest pharmacokinetic interactions for levomepromazine and melperone. In the pipamperone-group, lower MRs as well as higher plasma and C/D levels of RIS suggest potential interactions. © 2017 Elsevier Inc. All rights reserved.

1. Introduction Anxiety, agitation and sleep disturbances are common symptoms in patients with psychiatric disorders such as schizophrenia (Goodwin et al., 2003; Naidu et al., 2014). Besides the concomitant use of benzodiazepines for anxiolytic effects in acute states, a very common clinical practice implies the addition of low-potency antipsychotics (Higashima et al., 2004). Combining low-potency antipsychotics with first or second generation antipsychotics is lacks the risk of dependence, withdrawal and recurrence of anxiety following cessation of the treatment (Sim et

⁎ Corresponding author at: Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany. E-mail address: [email protected] (G. Schoretsanitis). 1 MP and GS contributed equally to this paper.

http://dx.doi.org/10.1016/j.pnpbp.2017.03.002 0278-5846/© 2017 Elsevier Inc. All rights reserved.

al., 2015). Moreover, possible pharmacodynamic interactions including amplified dopaminergic and noradrenergic blockade may prevent psychotic relapses (Nishikawa et al., 1985). Widely prescribed low-potency antipsychotics include chlorprothixene, levomepromazine, melperone, pipamperone and prothipendyl. These drugs show an efficient sedative potential and are often incorporated into a tailored antipsychotic treatment regimen (Waldfahrer, 2013). However, psychopharmacological treatment strategies may give rise to pharmacokinetic drug-drug interactions (DDI) that prominently increase the likelihood of adverse drug reactions, not only demonstrated by case reports (Chandran et al., 2003; Sarro, 2011). Consequently, knowledge about both, pharmacodynamic as well as pharmacokinetic interactions, is mandatory especially in the treatment of elderly patients, who are more vulnerable to unwanted side effects (Juurlink et al., 2003). Aim of the study was to compare plasma concentrations, dose-adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS and active moiety

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(RIS + 9-OH-RIS) as well as metabolic ratios between the co-medicated groups and the control group to account for potential pharmacokinetic interactions between low-potency antipsychotics and the CYP 2D6 metabolized risperidone. Chlorprothixene is a commonly used low-potency first generation tricyclic antipsychotic of the thioxanthene class for the management of agitation, primarily acting as a high affinity antagonist at dopamine D1-, D2-, D3-, serotonin 5-HT2-, histamine H1-, α1-adrenergic- and acetylcholine M1-receptors (Hiemke and Pfuhlmann, 2012). It has been reported to inhibit cytochrome P450 CYP2D6 as well as P-glycoprotein (Bader et al., 2008; Taur et al., 2012). A case report detected increased serum concentrations of risperidone's active moiety under a concomitant medication with chlorprothixene (Bader et al., 2008). Levomepromazine, also known as methotrimeprazine, is a low-potency antipsychotic of the phenothiazine class. Its anxiolytic, antiemetic, analgesic and sedative properties lead to its wide usage in palliative care (Bush et al., 2014; Dietz et al., 2013). It is acting with antagonistic properties at H1-, M1-, D2-, α1- and 5HT2-receptors (Lal et al., 1993). The α1blockade may contribute to its cardiovascular side effects (Sahlberg et al., 2015) that are luckily rarely reported for doses below 100 mg/day. Data support efficacy for the treatment of agitation in patients with schizophrenia (Higashima et al., 2004). The N-methylation of levomepromazine is mediated by CYP3A4 (Wojcikowski et al., 2014), while there is evidence for an inhibiting effect of levomepromazine on distinct CYP isoenzymes but primarily on CYP2D6 activity (Balant-Gorgia et al., 1986; Suzuki et al., 1997). Melperone is a butyrophenone derivative with antipsychotic, anxiolytic and sedative properties. Its main effect includes a weak dopamine D2-blockade and a strong antiserotonergic activity (5-HT2A) (Meltzer et al., 1989). The metabolic pathway of melperone has not been elucidated yet (Koppel et al., 1988). Regarding interactions in CYP mediated pathways, in vivo data support inhibiting effects on CYP2D6 activity; and data confirm that melperone alters the plasma concentrations of CYP2D6 substrates such as risperidone, nortriptyline and venlafaxine (Grözinger et al., 2003; Hefner et al., 2014; Hefner et al., 2015; Kohnke et al., 2006). Pipamperone is another low-potency antipsychotic drug of the butyrophenone family. In addition to its weak dopamine D2-receptor blockade, it exerts a prominent antagonistic effect at 5-HT2-receptors (Awouters and Lewi, 2007). Neither the mechanisms mediating the metabolism of pipamperone nor pharmacokinetic interactions are known so far (Hiemke and Pfuhlmann, 2012). Prothipendyl is a tricyclic low-potency antipsychotic of the azaphenothiazine group with sedating, antihistaminergic and antiemetic properties. Due to a very low affinity at the dopamine D2-receptor, extrapyramidal symptoms are rare even at high doses, while a strong torsadogenic signal may be produced (Raschi et al., 2013). Very little is known about its metabolic pathway and its potential of pharmacokinetic interactions (Hiemke and Pfuhlmann, 2012). Risperidone (RIS), a benzisoxazole derivative, is a second generation antipsychotic with antagonistic properties at serotonin 5-HT2- and dopamine D2-receptors (Janssen et al., 1988). RIS has been used effectively in the treatment of a broad spectrum of psychiatric diseases including schizophrenia (Chouinard and Arnott, 1993; Leucht et al., 1999; Marder et al., 1997). The primary pathway of RIS (half life time 3 h) metabolism is a CYP2D6-catalyzed 9-hydroxylation and the main active metabolite is 9-hydroxyrisperidone (9-OH-RIS) with a much longer half-life time of 21-30 h. In vitro findings have revealed that CYP3A4 and CYP3A5 might be also involved in the metabolism of risperidone (Fang et al., 1999; Xiang et al., 2010; Yasui-Furukori et al., 2001). As 9-OH-RIS is pharmacologically active, clinicians consider the combined concentration of RIS and 9-OH-RIS (active moiety, AM) as the most relevant measure. According to the AGNP consensus guidelines (Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie), a therapeutic reference range is suggested as 20–60 ng/mL for the active moiety (Hiemke et al., 2011).

2. Experimental procedures A large TDM database as part of KONBEST, a web-based laboratory information management system for TDM-laboratories (Haen, 2011) containing plasma concentrations of RIS and 9-OH-RIS of 1584 patients was analyzed. Data collection took place between 2006 and 2015 as part of the clinical routine in different institutions as part of the AGATE, ‘Arbeitsgemeinschaft Arzneimitteltherapie bei psychischen Erkrankungen’, a cooperation for drug safety in the treatment of psychiatric diseases, (for details: www.amuep-agate.de). Retrospective analysis of clinical data for this study was in accordance with the local regulatory authority of RWTH Aachen University hospital and in alignment with the Declaration of Helsinki. In this naturalistic database, patients were under medication with risperidone (RIS) for different reasons, only patients with organic mental disorders were excluded. Patients that received depot formulations and patients that were under concomitant medication with possible CYP2D6 inhibitory or CYP3A4 inhibitory or inducing properties were also excluded from analysis as well as samples with missing data of RIS, its pharmacokinetic parameters or clinical response (Hiemke et al., 2011, US Food and Drug Administration, 2014). Finally, 1074 out of 1584 patients met the inclusion criteria. We considered six groups; a group of patients that received RIS without a potentially cytochrome influencing co-medication (control group, R0), a group receiving a combination of risperidone and chlorprothixene (RCHLOR), a group comedicated with levomepromazine (RLEV), a group co-medicated with melperone (RMEL), a fourth with pipamperone (RPIP) and a fifth group, co-medicated with prothipendyl (RPRO). No matching processes for age, diagnoses, severity of illness, length or onset of illness were undertaken. 2.1. Quantification of risperidone and 9-OH-risperidone Blood was asked to be drawn just before drug administration (trough concentration) at steady state (N 5 elimination half-lives under the same drug dose). Risperidone and 9-OH-risperidone concentrations were determined by HPLC with ultraviolet detection (HPLC/ UV) (Bader et al., 2005). The method was validated according to DIN 32645 (Deutsche Industrie Norm 32645, described in guidelines of GTFCh (Society of Toxicology and Forensic Chemistry) in consideration of ISO 5725 (International Organization for Standardization) (Paul et al., 2009), FDA (US Food and Drug Administration) guidances (US Food and Drug Administration, 2001) and ICH (International Conference on Harmonization) requirements (International Conference on Harmonization, 1996). The laboratory regularly runs internal quality controls and participates in external quality assessment schemes by INSTAND (Düsseldorf, Germany, www.instandev.de). 2.2. Statistical analysis Our primary outcome was the active moiety plasma levels, which are considered of major clinical relevance (Hiemke et al., 2011). We compared the medians and the distributions of the plasma concentration of the parent compound, RIS, the active metabolite, 9-OH-RIS, as well as the active moiety (RIS + 9-OH-RIS) between the defined groups. Further comparisons included the plasma concentration corrected by the daily dose, defined as the dose-adjusted plasma concentration or ‘concentration-by-dose’, (C/D), and the ratios of 9-OH-RIS/RIS for the identification of the metabolizer status phenotype. Both were calculated in accordance with the AGNP consensus guidelines (Hiemke et al., 2011). Histograms yielded evidence of non-normal distributions, so that a nonparametrical Kruskal-Wallis test (K-W) with a significance level of 0.05 was conducted. To conduct pairwise comparisons (co-medication groups vs control group) a Mann Whitney U test with the same significance level was used. Statistical analysis was carried out using IBM SPSS Statistics version 18.0 (IBM GmbH, Ehningen, Germany).

M. Paulzen et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 76 (2017) 101–106 Table 1 Patients' demographic characteristics. Group

RCHLOR RLEV RMELP RPIP RPRO R0

Number

67 32 46 64 24 852

Age (years)

40.44 (19–72) 44.43 (19–83) 43.45 (20–79) 47.81 (18–81) 42.41 (22–78) 41.25 (18–87)

Gender

DD RIS (mg/day)

% Females

% Males

Median (range)

43.3 31.3 30.4 50.0 37.5 44.2

56.7 68.8 69.6 50.0 62.5 55.8

4.0 (1.00–9.0) 6.0 (2.00–10.0) 4.0 (1.00–10.0) 4.0 (1.00–10.0) 4.0 (1.00–10.0) 4.0 (1.00–10.0)

3. Results Data of the patients that were enrolled in the analysis were assigned to the six groups, R0 (n = 842), RCHLOR (n = 67), RLEV (n = 32), RMELP (n = 46), RPIP (n = 63), and RPRO (n = 24). The demographic data are summarized in Table 1. The median plasma concentrations (ng/mL) of RIS, 9-OH-RIS, the active moiety (RIS + 9-OH-RIS), as well as the metabolic ratios (9-OH-RIS/ RIS) are displayed in Table 2. Table 3 shows the dose-adjusted plasma concentrations, C/D [ng/mL/ mg], for RIS, 9-OH-RIS, and RIS + 9-OH-RIS for each of the six groups. Due to the skewness of the distribution, we conducted comparisons based upon the Kruskal-Wallis test (K-W). The median daily dosage of RIS did not differ between the six groups (p = 0.16) (mean 4.31 mg/d, SD = 2.02 for R0, 4.93 mg/d, SD = 2.09 for RCHLOR, 5.31 mg/d, SD = 2.13 for RLEV, mean 4.59 mg/d, SD = 2.20 for RMELP, mean 4.18 mg/d, SD = 2.11 for RPIP, and 5.06 mg/d, SD = 2.91 for RPRO. The comparison of the distribution (subscript indices ‘D’) and the medians (subscript indices ‘M’) of the plasma concentrations of RIS, 9-OH-RIS, and the active moiety (RIS + 9-OH-RIS) between the six groups yielded significant differences in all cases except the plasma concentration of the active metabolite and its dose-adjusted plasma concentration (9-OH-RISD, p = 0.339, C/D 9-OH-RISD, p = 0.59); (9OH-RISM, 0.342 and C/D 9-OH-RISM, p = 0.165). In all other cases of plasma concentrations and dose-adjusted plasma concentrations differences were significant (RISD, p b 0.001, RIS + 9-OH-RISD, p b 0.001, C/D RISD, p b 0.001 and C/D RIS + 9-OH-RISD, p b 0.001); the comparison of medians yielded similar findings (RISM, p b 0.001, RIS + 9-OH-RISM, p = 0.01, C/D RISM, p b 0.001 and C/D RIS + 9-OH-RISM, p = 0.001). Furthermore, the metabolic ratios (9-OH-RIS/RIS) differed between the six study groups (9-OH-RIS/RISD, p b 0.001, 9-OH-RIS/RISM, p b 0.001). 3.1. Pairwise comparison between treatment groups To control for significant differences between pairs of groups (R0 vs. RCHLOR; R0 vs. RLEV; R0 vs. RMELP; R0 vs. RPIP; and R0 vs. RPRO) with regard to the distributions, a Mann-Whitney U test was used (See Figs. 1 and 2).

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Comparing RCHLOR vs. R0 yielded significant differences in the case of plasma concentration of the parent compound, RIS, (p = 0.037), where values were higher in the chlorprothixene group. This difference did not remain significant in case of dose-adjusted plasma concentrations (C/D RIS) (p = 0.434). Plasma concentrations and their C/D value neither differed in case of the active metabolite (p = 0.366 and p = 0.384) nor in the case of the active moiety (p = 0.082 and p = 0.719). Moreover, metabolic ratios did not present significant differences between the two groups (p = 0.235). The comparison of RLEV with R0 yielded significant differences in all values except the plasma concentration and C/D of 9-OH-RIS (p = 0.185 and p = 0.445). Plasma concentrations and C/D of the parent compound were higher in the levomepromazine group (p b 0.001 and p b 0.001), as well as plasma concentrations of active moiety and C/D AM (p b 0.001 and p b 0.001). Contrastingly, metabolic ratios were lower in the levomepromazine group (p b 0.001). Similarly, the comparison of RMELP with R0, revealed significant differences for all parameters between the groups except the plasma concentration and C/D of 9-OH-RIS (p = 0.366 and p = 0.863), while plasma concentrations and C/D of RIS were higher in patients that were co-medicated with melperone (p = 0.001 and p b 0.001). Plasma concentrations and C/D of the active moiety were higher in the melperone group (p = 0.01 and p = 0.018) while the metabolic ratios were higher in the control group (p = 0.003). In case of RPIP, significant distribution differences were detected in case of plasma concentration of RIS (p = 0.01) and C/D RIS (p = 0.004), with patients in the RPIP group showing higher values for both but lower metabolic ratios (p = 0.011). No significant differences were observed in case of plasma concentrations and dose-adjusted plasma concentrations of 9-OH-RIS (p = 0.393 and p = 0.181) and active moiety (p = 0.302 and p = 0.149). The comparison of RPRO vs R0 revealed significant differences only in case of the plasma concentration of RIS (p = 0.02) with higher values in the RPRO group. However, this difference wasn't replicated by the comparison of the C/D values of RIS (p = 0.09). No significant differences were detected in case of plasma concentrations of 9-OH-RIS and C/D 9-OH-RIS (p = 0.116 and p = 0.593) as well as in case of plasma concentrations of the active moiety and C/D AM (p = 0.079 and p = 0.274). Furthermore, differences for metabolic ratios did not reach statistical significance (p = 0.237). 4. Discussion The addition of low-potency antipsychotics to an ongoing antipsychotic treatment is a common strategy offering various therapeutic benefits (Podea et al., 2015). However, the pharmacodynamic and the pharmacokinetic impact of such treatment regimens remains unclear. Its elucidation might minimize the risk of commonly reported adverse events such as confusion, excess sedation and extrapyramidal

Table 2 Median plasma concentrations (range) and metabolic ratios of risperidone in the study groups. Group

RIS

9-OH-RIS

RIS + 9-OH-RIS

9-OH-RIS/RIS

RCHLOR RLEV RMELP RPIP RPRO R0

7.3 (0.3–47.0)⁎ 32.0 (2.1–165.0)⁎⁎ 8.7 (0.3–114.0)⁎⁎⁎ 6.6 (0.4–73.0)⁎⁎⁎⁎ 7.5 (0.8–41.0)⁎⁎⁎⁎⁎

20.0 (1.8–88.0) 19.0 (2.0–147.0) 17.4 (2.1–67.0) 20.0 (1.4–83.5) 23.5 (0.4–63.0) 17.0 (0.3–196.5)

31.0 (3.5–122.0) 47.5 (13.8–231.0)⁎⁎ 35.9 (4.8–133.0)⁎⁎⁎ 28.0 (2.8–144.4) 33.0 (7.5–84.0) 24.0 (1.8–264.0)

3.18 (0.15–38.0) 0.6 (0.06–15.2)⁎⁎ 1.96 (0.17–70.0)⁎⁎⁎ 2.2 (0.23–25.0)⁎⁎⁎⁎ 3.3 (0.02–8.3) 3.8 (0.04–290.0)

4.4 (0.1–224.0)

⁎ Plasma concentrations for RIS in the RCHLOR group were significantly higher than in the control group (p = 0.041 for Mann-Whitney U Test). ⁎⁎ Plasma concentrations for RIS and RIS + 9-OH-RIS in the RLEV group were significantly higher, while metabolic ratios were lower than in the control group (p b 0.001, p b 0.001 and p b 0.001 for Mann-Whitney U Test). ⁎⁎⁎ Plasma concentrations for RIS and RIS + 9-OH-RIS in the RMELP group were significantly higher, while metabolic ratios were lower than in the control group (p = 0.001, p = 0.011 and p = 0.003 for Mann-Whitney U Test). ⁎⁎⁎⁎ Plasma concentrations for RIS in the RPIP group were significantly higher, while metabolic ratios were lower than in the control group (p = 0.008 and p = 0.009 for Mann-Whitney U Test). ⁎⁎⁎⁎⁎ Plasma concentrations for RIS in the RPRO group were significantly higher than in the control group (p = 0.022 for Mann-Whitney U Test).

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Table 3 Median dose-adjusted plasma concentrations (C/D) of risperidone in the different groups. Group

C/D RIS

C/D 9-OH-RIS

C/D RIS + 9-OH-RIS

RCHLOR RLEV RMELP RPIP RPRO R0

1.33 (0.10–14.50) 5.33 (0.70–27.50)⁎ 2.57 (0.05–14.4)⁎⁎ 1.59 (0.20–20.30)⁎⁎⁎ 1.87 (0.27–24.00) 1.16 (0.02–74.67)

4.00 (0.48–22.0) 3.45 (0.50–26.33) 4.41 (1.10–37.0) 4.93 (0.83–27.83) 4.42 (0.4–16.00) 4.33 (0.08–42.00)

5.87 (1.17–30.50) 10.12 (2.30–37.33)⁎ 8.02 (2.65–43.00)⁎⁎ 6.57 (1.25–48.13) 6.40 (2.50–24.40) 6.29 (0.5–88.0)

⁎ Corrected by dosage values (C/D) for RIS and RIS + 9-OH-RIS in the RLEV group were significantly higher from the control group (p b 0.001 and p b 0.001 for Mann-Whitney U Test). ⁎⁎ Corrected by dosage values for RIS and RIS + 9-OH-RIS in the RMELP group were significantly higher from the control group (p b 0.001 and p = 0.017) for Mann-Whitney U Test). ⁎⁎⁎ Corrected by dosage values for RIS in the RPIP group were significantly higher from the control group (p = 0.004 for Mann-Whitney U Test).

symptoms (Wilkinson, 2005). Our findings may facilitate the improvement of the efficacy and safety of combined antipsychotic treatments with regard to pharmacokinetic aspects. Comparisons were conducted between groups of patients with similar median daily dosages of risperidone so that possible differences in plasma concentrations and doseadjusted plasma concentrations of RIS, 9-OH-RIS and AM cannot be attributed to differences in the applied dosage. Obviously, the addition of levomepromazine and/or melperone have the greatest impact on the metabolism of risperidone. Patients who were co-medicated with levomepromazine showed lower metabolic ratios than patients in the control group. Combining this finding with the observed increase in plasma concentrations and dose-adjusted plasma concentrations of the clinically relevant active moiety as well as of the RIS, suggests a strong inhibiting effect of levomepromazine on risperidone metabolism. Several finding in the literature suggest an inhibiting effect of levomepromazine on CYP2D6 activity leading to reduced metabolite concentrations of CYP2D6 substrates including various psychopharmacological agents like antipsychotics (risperidone, haloperidol) and antidepressants (clomipramine, citalopram) (Balant-Gorgia et al., 1986, Gram et al., 1993, Mannheimer et al., 2008, Suzuki et al., 1997). More specifically, Mannheimer and colleagues detected significant differences of pharmacokinetic parameters of risperidone other than the active metabolite in a group of patients under a combined treatment with risperidone and levomepromazine comparing to other groups under risperidone and other psychotropic agents (Mannheimer et al., 2008). A CYP2D6 mediated inhibiting effect of levomepromazine on risperidone metabolism might plausibly explain the higher plasma concentrations of RIS in our study as well as the lower metabolic ratios. CYP2D6 inhibitors have been admittedly reported to exert a stronger effect on risperidone metabolism than that of its metabolite (Calarge and Miller del, 2011). Hence, levomepromazine may alter the metabolism

Fig. 2. Comparison of the metabolic ratios (9-OH-RIS/RIS) between the different groups as an expression of the metabolizer status.

essentially by exerting strong inhibitory effects on CYP2D6 and thus leading to increased plasma concentrations of the parent compound RIS. Active moiety plasma and C/D concentrations were also higher in patients co-medicated with melperone, who demonstrated higher plasma and C/D concentrations of RIS as well. Combined with the lower metabolic ratios in the melperone group this finding implies an inhibiting effect of melperone on the CYP2D6 mediated metabolism of risperidone. This evidence validates the findings of a series of case reports, showing a reduced metabolism of risperidone in patients under concomitant medication with melperone (Kohnke et al., 2006). The finding is in line with a recently published study by Hefner et al. revealing enhanced venlafaxine plasma concentrations and lower metabolic ratios in patients who were co-medicated with melperone under an ongoing treatment with venlafaxine (Hefner et al., 2015). Grözinger et al. validated the hypothesis of inhibiting effects of melperone on CYP2D6 activity by investigating the effect of melperone on the metabolism of dextromethorphan (Grözinger et al., 2003). Hence, the co-administration of melperone may be of critical clinical significance for any CYP2D6 metabolized (psychotropic) drugs and should always be evaluated from a pharmacokinetic view before administering to an ongoing treatment with CYP2D6 substrates. The evidence in case of pipamperone may answer some critical questions for the still unraveled pharmacokinetic mechanism of this drug. The co-prescription of pipamperone in patients under a treatment with risperidone led to enhanced dose-adjusted plasma concentrations

Fig. 1. Median plasma concentrations of RIS (A), 9-OH-RIS (B) and active moiety (C) in the different study groups.

M. Paulzen et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 76 (2017) 101–106

of RIS. However, this upturn did not show up in dose-adjusted plasma concentrations of the active moiety, where differences did not reach statistical significance. This may illustrate a rather slight inhibiting effect of pipamperone on risperidone metabolism, which was further implied by the lower metabolic ratio in the pipamperone group (p = 0.009). However, no conclusion can be drawn whether the effect is mediated by CYP2D6 inhibiting properties of pipamperone or by inhibitory effects on CYP3A. The dearth of clinical studies and case reports in the literature as well as the weakness of the interacting effect don't allow further clarification of the exact mechanism underlying this finding or/and its clinical significance. Analyzing both, the chlorprothixene and the prothipendyl groups showed comparable findings. In both groups patients did not show differences regarding the pharmacokinetic parameters of risperidone when compared to the control group other than in case of plasma concentration of the parent compound. This difference did not remain significant after correction for the daily dosage. Metabolic ratios also showed no difference in both groups compared with the control group. The clinical significance of these findings can be disputed. Thus, chlorprothixene and prothipendyl were rather unlikely to alter the metabolism and therefore the pharmacokinetic parameters of risperidone. To our knowledge, there is barely evidence of interactions of these two drugs with other medication of the same or different pharmacological class. A single case report detected enhanced serum levels of risperidone active moiety under concomitant medication with chlorprothixene (Bader et al., 2008). However, in that case the patient was receiving a long acting form of risperidone, where different patterns of pharmacokinetic interactions might be involved (Castberg and Spigset, 2005; Ereshefsky and Mascarenas, 2003). Based upon this data and from a pharmacokinetic point of view, it should be taken into account that the addition of levomepromazine or melperone to an ongoing treatment with risperidone may lead to changes in dose-adjusted plasma concentrations. This insight might reveal a comparative disadvantage when levomepromazine and melperone are considered as a co-medication. Low-potency antipsychotic agents are widely assumed as a safe and very well tolerable option especially in elderly patients; however, possible interactions, presumably mediated by the cytochrome P450 pathway, have to be considered in order to minimize adverse and/or unwanted effects. According to our data from a pharmacokinetic point of view, other low-potency antipsychotics such as chlorprothixene or prothipendyl are less likely to interact with risperidone and could therefore be a more favorable choice in treating agitation and/or insomnia in patients with schizophrenia. 5. Limitations Our sample comprised a large naturalistic population and relies on retrospective data. Thus, patient information could be considered less reliable than in case of a prospective study. A significant amount of clinical parameters including onset and duration of illness, response scales and adverse effects, comorbidities, duration of treatment with the investigated antipsychotics were not available and therefore further analyses could not be undertaken. Furthermore, there might be a considerable individual variation in sampling time as a result of the clinical setting, which may have partially accounted for the pronounced interindividual variation in plasma concentrations and metabolic ratios. In the case of multiple plasma concentration determinations we minimized the patient bias by including only the most recent analysis of every patient. Regarding the analyses of the data, we observed differences in sample characteristics and sample size in the six patient groups; thus the comparability of the study groups with the control group might present some restrictions. Consequently, we avoided to stratify for age despite the well-known effect of age on risperidone metabolism (Feng et al., 2008). Despite the remarkably bigger size of the control group, we chose not to reduce our control group taking into

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account the extent of the skewness of the sample distribution. In order to eliminate confounding factors of pharmacokinetic nature on plasma concentration we excluded patients under concomitant potent modulators of CYP activity from the analysis. Role of the funding source There was not fund for this study. Ekkehard Haen received speaker's or consultancy fees from the following pharmaceutical companies: Servier, Novartis, and Janssen-Cilag. He is managing director of AGATE, a non-profit working group to improve drug safety and efficacy in the treatment of psychiatric diseases. He reports no conflict of interest with this publication. Christoph Hiemke has received speaker's or consultancy fees from the following pharmaceutical companies: Astra Zeneca, Janssen-Cilag, Pfizer, Lilly and Servier. He is managing director of the psiac GmbH which provides an internet based drug–drug interaction program for psychopharmacotherapy. He reports no conflict of interest with this publication. Gerhard Gründer has served as a consultant for Boehringer Ingelheim (Ingelheim, Germany), Cheplapharm (Greifswald, Germany), Eli Lilly (Indianapolis, Ind, USA), Lundbeck (Copenhagen, Denmark), Ono Pharmaceuticals (Osaka, Japan), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers' bureau of Eli Lilly, Gedeon Richter (Budapest, Ungarn), Janssen Cilag (Neuss, Germany), Lundbeck, Roche, Servier, and Trommsdorf (Aachen, Germany). He has received research support from Boehringer Ingelheim and Roche. He is co-founder of Pharma Image GmbH (Düsseldorf, Germany) and Brainfoods UG (Selfkant, Germany). He reports no conflict of interest with this publication. Georgios Schoretsanitis received grant from the bequest “in memory of Maria Zaoussi”(Reg. Nr: 2015-0091-1467), State Scholarships Foundation, Greece for clinical research in Psychiatry for the academic year 2015-2016. All other authors declare no conflicts of interest as well. The research study did not receive funds or support from any source. Authorship contributions Participated in research design: GS; MP, GG, CH, EH, BS, KRJS. Performed data analysis: GS, MP, SEL. Wrote or contributed to the writing of the manuscript: GS; MP, GG, SW, CH, EH, BS, KRJS, SEL. Acknowledgments The authors wish to express their gratitude to the number of people who contributed with excellent professional technical as well as pharmacological competence to build up the KONBEST data base with 50.049 clinical pharmacological comments as of February 2, 2016 (ranked among the professional groups in historical order): A. Köstlbacher created the KONBEST software in his Ph.D. thesis based on an idea of E. Haen, C. Greiner, and D. Melchner along the work flow in the clinical pharmacological laboratory at the Department of Psychiatry and Psychotherapy of the University of Regensburg. He ongoing maintains together with his colleague A. Haas the KONBEST software and its data mining platform (Haas & Köstlbacher GbR, Regensburg/Germany). The lab technicians performed the quantitative analysis: D. Melchner, T. Jahner, S. Beck, A. Dörfelt, U. Holzinger, and F. PfaffHaimerl. The clinical pharmacological comments to drug concentrations were composed by licensed pharmacists and medical doctors: Licensed pharmacists: C. Greiner, W. Bader, R. Köber, A. Hader, R. Brandl, M. Onuoha, N. Ben Omar, K. Schmid, A. Köppl, M. Silva, B. Fay, S. Unholzer, C. Rothammer, S. Böhr, F. Ridders, D. Braun, M. Schwarz; M. Dobmeier, M. Wittmann, M. Vogel, M. Böhme, K. Wenzel-Seifert, B. Plattner, P. Holter, R. Böhm, R. Knorr.

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